Virus hepatitis B is a disease that is caused by hepatitis B virus (HBV), mainly characterized with inflammatory lesions of the liver, and can cause multiple-organ damage. Hepatitis B is widely prevalent throughout the world, mainly affecting children and young adults, and a small number of which may be transformed into liver cirrhosis or liver cancer. Therefore, it has become a worldwide disease that seriously threatens human health. It is also one of the most widespread and most harmful diseases. Virus hepatitis B does not have a certain epidemic period. It can develop throughout the year, and most of it develops sporadically. In recent years, the incidence of hepatitis B has increased significantly. Studies have shown that inhibition of HBV is directly related to the therapeutic effect of hepatitis B (see, e.g., Klaus Klumpp and Thibaut Crepin, Capsid proteins of enveloped viruses as antiviral drug targets, Current Opinion in Virology, 2014, 5: 63-71; Timothy M. Block, Siddhartha Rawat, Carol L. Brosgart, Chronic hepatitis B: A wave of new therapies on the horizon, Antiviral Research, 121, 2015, 69-81).
Although there are many methods for the treatment of hepatitis B virus infection, they are greatly limited. Only in very few patients, the continuous serum HBV DNA reduction, serological conversion of e antigen and s antigen and other treatment effects can be observed.
For example, interferon alpha has been widely used for the treatment of chronic HBV infection for many years, but interferon is only effective for specific types of patients and is poorly tolerated. Similarly, lamivudine (3′-thio-2′,3′-dideoxycytidine) has been used for the treatment of HBV infection because of its marked inhibitory effect on HBV replication, but due to the gradually increased resistance rates, the efficacy in a large proportion of patients is limited. Recently marketed adefovir dipivoxil (9-[2-[[bis[(pivaloyloxy)methyl]phosphinyl]methoxy]ethyl]adenine) is effective to the lamivudine-resistant patients, but the drug has the disadvantage that the sustained viral response rate is low (less than 20%) and the maximum tolerated dose and duration of treatment are often limited due to its nephrotoxicity.
Recent studies have found that a number of drugs have good anti-HBV activity and have entered clinical studies. For example, 2′-fluoro-5-methyl-β-L-uracil arabinoside (Bukwang), 2′-deoxy-5-fluoro-3′-thiocytidine (Gilead), 2′-deoxy-L-thymidine (Idenix), 2′-deoxy-L-cytidine (Idenix) and other nucleosides showed significant anti-HBV activity. In addition, cyclic nucleoside compounds such as 2-amino-1,9-dihydro-9[(1 S ,3 R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopent yl]-6H-purine-6-one monohydrate (Bristol-Myers Squibb) and liver-targeting acyclic nucleoside compounds such as Ribapharm are also clinically active against HBV.
Although most of the recently discovered anti-HBV drugs exhibit good in vitro antiviral activity, low response rates and resistance limit the clinical effectiveness of these drugs. Therefore, although there are currently many drugs and methods for treating HBV, novel or improved drugs and methods of treatment are still clinically needed.
In summary, the existing therapeutic drugs for HBV have the limitations of limited therapeutic effect, easy drug resistance and high toxicity. Therefore, there is an urgent need for new drugs with high efficacy, low toxicity, and different drug resistance profiles clinically.